The primary long term objective of this proposal is to critically evaluate in the clinic novel therapies for a range of human malignancies. This will be accomplished by performing high quality Phase II scientifically- directed trials with novel anti-cancer therapies. This proposal is designed to combine and focus the extensive resources, experience and capabilities of a broad range of.clinical and laboratory investigators within the Johns Hopkins Oncology Center. This will be accomplished because of a number of critical strengths which will be effectively coordinated by the proposal. These include (l) a large active multi- disciplinary clinical research program emphasizing new drug development, breast cancer, aerodigestive tract-tumors, bone marrow transplantation, lung cancer, leukemia, gastrointestinal and genitourinary malignancies, (2) a broad range of laboratory programs in areas such as tumor genetics, pharmacology, drug resistance, tumor immunology and gene therapy, hematopoiesis, marrow transplantation, programmed cell death and tumor metastasis which relate directly to the clinical programs, (3) exceptional expertise in clinical trial design, statistics and data management and (4) a proven track record in the design and implementation of innovative therapeutic trials combining novel treatments with close laboratory correlations. This proposal augments these strengths by defining an organizational structure which will, (1) facilitate optimal study design by input from the Biostatistics and Pharmacology Cores at an early stage of protocol design, (2) incorporate an expert Scientific Core to review, evaluate, modify and select protocols for submission to CTEP under this mechanism and, (3) monitor and ensure strict adherence to RFA guidelines, accrual goals, protocol eligibility, quality control, study monitoring and data collection, management and analysis. Three protocols are submitted with this proposal. which reflect the strengths of the application. These comprise a study of topotecan in adult ALL with analysis of leukemia cell topoisomerase and MDR levels, a trial of the combination of taxol and cyclophosphamide in women with breast cancer with tissue biopsies to evaluate mechanisms of resistance and a study of novobiocin to reverse alkylating agent drug resistance in women with metastatic breast cancer undergoing high-dose chemotherapy.